Vascular stent construction begins with a scaffold, a spring-like device which props open the lumen of an artery or vein following the performance of a procedure, such as an angioplasty, which is done to open a vessel narrowed by a disease such as atherosclerosis, without or with accompanying thrombosis. Thus far vascular stent construction has mainly involved scaffolds with metallic compositions. This has led to a first generation bare metal stent involving a scaffold only which has been followed by a second generation stent which elutes drugs for preventing restenosis. Drugs have either been directly applied to the scaffold of these stents or eluted from polymers coated onto the metallic scaffolds of stents. Drug eluting stents have largely solved the problem of restenosis; however, the drugs used, paclitaxel and mTOR or cell cycle inhibitors such as rapamicin, sirolimus, etc., have done this at the cost of causing endothelial dysfunction, impaired re-endothelization and stent thrombosis See Long et al., “FK506 Binding Protein 12/12.6 Depletion Increases Endothelial Nitric Oxide Synthase Threonine 495 Phosphorylation and Blood Pressure,” Hypertension, 49: 569-76 (2007); and Pendyala et al., “The First-Generation Drug Eluting Stents and Endothelial Dysfunction,” J. Am Coll Cardiol Intv, 2: 1169-77 (2009). This has led to a prolonged requirement for dual antiplatelet therapy with its inherent risk of bleeding.
Regarding antiplatelet therapy, current guidelines recommend 12 or more months of dual antiplatelet therapy following placement of a drug eluting stent. There currently is a need in the art for this period to be reduced to 3 months or less in order to reduce the risk of bleeding from prolonged antiplatelet drug therapy.
Recently a stent scaffold has been constructed from a polylactide polymer typically used to make bioresorbable sutures and other related bioresorbable surgical devices. See Capodanno et al., “Novel Drug-eluting Stents in the Treatment of de novo Coronary Lesions”, Vascular Health and Risk Management, vol. 7, pp 103-118 (2011). This scaffold has been used to fabricate a stent which elutes everolimus, an antirestenosis agent, from a biodegradeable polymer coated on the surface of the scaffold. This discovery has led to the development of a third generation stent which passively disappears from the vessel lumen over a period of one to two years and is thought to reduce the risk of stent thrombosis. However, the effect of this stent on the risk of stent thrombosis is currently unknown and under investigation in clinical trials. The bioresorbable vascular scaffold in this stent, unlike the scaffolds of the present invention, has no intrinsic pharmacologic biological activity.
Polylactide is a terpolymer of (a) L(−)lactide, (b) glycolide, and (c) epsilon-caprolactone. The L(−) lactide component varies from 45-85% by weight. Glycolide varies from 5-50% by weight. And the epsilon-caprolactone varies from about 15 to 25% by weight. The initial use of polylactide in bioresorbable stent construction was for urethral stents. See Goldberg et al., U.S. Pat. No. 5,085,629.
The process of synthesizing polylactide involves the presence of a lactone ring in epsilon-caprolactone. HMG CoA reductase inhibitors, or statins, likewise have structures that can exist in a form with a closed lactone ring. It has recently been shown that a statin can be polymerized with DL-lactide-glycolide to form polystatin containing microspheres which can be placed in a PolyRing for sustained perivascular drug delivery to vascular grafts and dialysis access devices to prevent intimal hyperplasia. See Krishnan, “Simvastatin Incorporated Perivascular Polymeric Controlled Drug Delivery System for the Inhibition of Vascular Wall Intimal Hyperplasia,” A Thesis Presented to The Graduate Faculty at The University of Akron. August, 2007. More recently, sustained simvastatin release from a poly(lactide-co-glycolide) membrane has been shown to have potential for use as a controlled release scaffold for bone tissue engineering. See Rashidi et al., “Simvastatin Release from Poly(lactide-co-glycolide) Membrane Scaffolds,” Polymers, vol 2, pp 709-718 (2010). This study utilized methods of an earlier study. See Benoit et al., “Synthesis and Characterization of a Fluvastatin-Releasing Hyrogel Delivery System to Modulate hMSC Differentiation and Function for Bone Regeneration. Biomaterials,” 27: 6102-10 (2006).
A bioresorbable polystatin for use in constructing scaffolds for vascular stents is attractive because with metabolism of the polystatin to its monomeric form which occurs in the bioresorption process, the action of the exuded statin to increase the activity of nitric oxide synthase is felt to reduce the risk of stent thrombosis and the need for post stent antiplatelet therapy with its risk of bleeding. See Kaesemeyer, “Statin DES for Early Stent Thrombosis,” Atherosclerosis. 207: 343 (2009); Kaesemeyer, U.S. Pat. No. 6,425,881; Jaschke et al., “Local Statin Therapy Differentially Interferes with Smooth Muscle and Endothelial Proliferation and Reduces Neointima on a Drug-Eluting Stent Platform,” Cardiovas Res, 68: 483-92(2005); and Miyauchi et al., “Effectiveness of Statin-Eluting Stent on Early Inflammatory Response and Neointimal Thickness in a Porcine Coronary Model,” Circ J. 72: 832-8 (2008). The same principal applies to any nitric oxide agonist possessing a lactone ring in its structure that will permit polylactide polymer formation.
A bioabsorbable polymer scaffold for a stent is taught by Johnson et al., US published Application No. 2008/0249608. The scaffold comprises a plurality of hoop components configured as the primary radial load bearing elements of the intraluminal scaffold; and one or more connector elements interconnecting the plurality of hoop components, wherein at least one of the plurality of hoop components and the one or more connector elements comprises a composite structure formed from a bioabsorbable metallic material and a bioabsorbable polymeric material. Although Johnson describes a plurality of therapeutic and pharmaceutic agents including a statin which can be coated on the scaffold, the Johnson scaffold does not include a statin incorporated into the polylactide polymeric scaffold, as taught according to embodiments of the present invention. And upon bioresorpton of the Johnson et al scaffold, the added drugs can exert their separate pharmacologic bioactivities but, overall, the scaffold illustrates extrinsic pharmacologic bioactivity instead of the intrinsic pharmacologic bioactivity seen with the scaffold of the present invention. And this is because the Johnson scaffold, minus the effects of the drugs added to the scaffold, has no “intrinsic” pharmacologic activity and does not function as a prodrug during the process of bioresorption, as does the scaffold described herein. Lastly, unlike the Johnson scaffold, the pharmacologically active agents in the scaffold of this invention are chemically bonded as monomers in the overall polymeric structure of the bioresorbable scaffold.
Lim et al., US published Application No. 2009/0306120, discloses an amorphous terpolymer comprising a lactide, a glycolide and caprolactone, which can be a coating on an implantable device for controlling the release of drugs or can be a bioabsorabable implantable device such as a bioabsorbable stent. Lim et al. disclose lists of biologically active agents including lovastatin (a drug that inhibits HMG-CoA reductase). Lim et al. does not teach a scaffold comprising a L(−) lactide—glycolide-statin terpolymer according to embodiments of the present invention. And upon bioresorpton of the Lim et al scaffold, the added drugs can exert their separate pharmacologic bioactivities but, overall, the scaffold illustrates extrinsic pharmacologic bioactivity instead of the intrinsic pharmacologic bioactivity seen with the scaffold of the present invention. The Lim scaffold, minus the effects of the drugs added to the scaffold, has no “intrinsic” pharmacologic activity and does not function as a prodrug during the process of bioresorption, as does the scaffold described herein. Lastly, unlike the Lim scaffold, the pharmacologically active agents in the scaffold of this invention are chemically bonded as monomers in the overall polymeric srtucture of the bioresorbable scaffold.